Pediatric Carbamazepine Toxicity 

Carbamazepine (Tegretol) has been used for the treatment of trigeminal neuralgias since 1960. Since carbamazepine received approval for use as an antiepileptic agent in the United States in 1974, it became widely used for the management of partial or tonic-clonic epilepsy. Carbamazepine is also used as a treatment for patients with manic-depressive illness, postherpetic neuralgia, and phantom limb pain. Some of the available dosage forms for carbamazepine include 100-mg and 200-mg oral tablets and a 100-mg/5-mL oral suspension.

The therapeutic plasma concentration is 4-12 mg/L. A peak plasma level is achieved in 6-24 hours. Controlled-release formulation could result in peak levels as late as 4 days after administration.^[1] The volume of distribution is 1-2 L/kg. Carbamazepine is approximately 75-80% protein bound, and approximately 2-3% is excreted unchanged in the urine. Carbamazepine is oxidized by hepatic microsomal enzymes to produce its active metabolite, carbamazepine 10,11-epoxide. The serum concentration of the epoxide metabolite is approximately 20% in children and 10-15% in adults.

Autoinduction of microsomal enzyme results in a shorter carbamazepine half-life (10-20 h) in patients who use the drug long-term compared with those with a short-term exposure (31-35 h). The autoinduction process takes about 4 weeks.

In terms of drug interactions, carbamazepine induces the metabolism of other anticonvulsant drugs such as phenytoin, clonazepam, primidone, valproic acid, and ethosuximide. This may lead to subtherapeutic levels of these drugs, especially phenytoin.

Inhibitors of hepatic microsomal enzymes, such as erythromycin, clarithromycin, and cimetidine, increase carbamazepine levels and may cause toxicity. Carbamazepine may increase the toxicity of adenosine and may increase the risk of heart block. Lower initial doses of adenosine should be used in patients who are taking carbamazepine.

Carbamazepine is a complex drug that has both anticonvulsant properties in therapeutic doses and a proconvulsant property in overdose situations with supratherapeutic serum levels. Carbamazepine is chemically and stereospatially related to the tricyclic antidepressant (TCA) imipramine; it is spatially similar to phenytoin. The therapeutic anticonvulsant mechanism of carbamazepine is similar to phenytoin and is believed to be primarily related to the blockade of presynaptic voltage-gated sodium channels.

Blockage of sodium channels is believed to inhibit the release of synaptic glutamate and possibly other neurotransmitters. It also inhibits N -methyl-D-aspartate (NMDA) receptors and CNS adenosine receptors. Carbamazepine also has powerful anticholinergic properties through inhibition of the muscarinic and nicotinic acetylcholine receptors. The seizures that occur with carbamazepine toxicity are largely secondary to a central anticholinergic syndrome. The coma and respiratory depression associated with overdose may be related to sodium channel suppression of neurotransmission. Carbamazepine causes antagonism at the adenosine subtype A1 receptor and agonism at the adenosine subtype A2 receptor. In lower therapeutic doses, this may be partially responsible for the anticonvulsant effect, whereas, in overdose situations, it may increase sedation or precipitate coma.

Cardiac arrhythmias due to carbamazepine are related to its sodium channel and anticholinergic effects. In therapeutic doses, the cardiovascular sodium channels are only minimally affected, and carbamazepine does not appear to be proarrhythmic. However, in overdose situations, carbamazepine produces sodium channel blockade effects similar to those of TCAs.

Frequency

United States

Because of widespread use of carbamazepine in patients with pediatric epilepsy, the incidence of carbamazepine poisoning is increasing in all age groups. In 1997, the American Association of Poison Control Centers recorded 7151 cases of carbamazepine intoxication.^[1]

Mortality/Morbidity

In 2007, among 4,255 exposures to carbamazepine, 78 patients had a major toxicity, and 1 death was reported.^[1] Complications of severe poisoning include coma, respiratory depression, seizures, hypotension, and GI hypomotility. Cardiac toxicity is uncommon in children, especially in those who have a structurally normal heart.

Sex

No specific sex predilection has been noted.

Age

Of the 2230 cases of carbamazepine toxicity reported by the American Association of Poison Control Centers in 2004, 660 were reported among children younger than 6 years, 380 were reported among children aged 6-19 years, and 1,190 were reported in individuals older than 19 years.^[1] Most pediatric patients are younger than 6 years.